HIV-1 encodes the transactivting protein Tat, which is essential for virus replication and progression of HIV disease. Studies were performed to understand the mechanisms by which HIV-Tat regulates cellular and viral effects in HIV-infected cells. Recent findings from our laboratory suggest that cellular activation by Tat involves a short core domain, Tat21-40, containing only 20 amino acid residues highly conserved in most HIV-1 subtypes. Effective induction by Tat21-40 and basic domain Tat53-68 of both nuclear factor-kB-mediated HIV replication and TAR-dependent transactivation of the HIV-LTR indicates that these short sequences are sufficient to promote HIV infection. These findings are potentially important to understand the progression of HIV pathogenesis and in the development of potential therapeutic applications. We now plan to study: (a) understand molecular mechanisms involved in HIV-Tat-mediated immune dysregulation;(b) develop diagnostic tools for the detection of extracellular Tat protein in blood/blood products, which if remain undetected by limited diagnostic tools currently available, may cause detrimental effects to the blood/blood product recipients; and (c) develop strategies to use HIV-Tat as a therapeutic vaccine candidate against AIDS. These studies may also help defining a role of HIV-Tat in seropositive non-progressors who have high titer of anti-Tat antibodies with a substantially low viral load.